Au团簇-多肽探针设计及其靶向整合素分子机制的理论模拟研究

Recently, noble metal cluster-peptide probes are applied broadly in life science and biomedicine fields. However, there is a bottleneck in the design and construction of nanoprobes. Till now, the influence of noble metal cluster is still not able to be considered in the peptide screening experiments. This limits the targeting validity and investigation efficiency badly. Thus, it is of fundamental scientific importance to design novel nanoprobe and investigate its targeting detection mechanism in live cells. Meanwhile, there are many factors can regulate the targeting performance of nanoprobe, which makes the study of the targeting detection principle be a new hot frontier full of challenges. In this project, we plan to study the typical detection system of Au cluster-peptide probe targeting integrin αIIbβ3 theoretically. We focus on the molecular mechanism of targeting detection by investigating the specific binding mode and binding stability of nanoprobe with its targeting protein. Here, we choose the new generation ligand γC peptide of integrin αIIbβ3 as the design starting point. We aim to design and construct a series of novel Au cluster-peptide probes targeting integrin αIIbβ3 properly, which can be combined with the experimental study. This process plays the crucial roles in solving the scientific core problem of targeting detection principle in live cells. Furthermore, integrin is related to many major diseases tightly, so our study is helpful for the early diagnosis and timely treatment of these diseases, and has important practical value.

贵金属团簇-多肽探针在生命科学、生物医学领域具有广阔应用前景，然而探针的设计构建研究却面临瓶颈问题。目前筛选靶向多肽实验无法考虑贵金属团簇的影响，大大限制探针靶向有效性和研究效率。因此，针对纳米探针的优化设计、及其靶向检测分子机制的理论模拟研究显得尤为重要。又因探针的靶向性受多种因素调控，使上述研究成为具有挑战性的新热点。本项目针对Au团簇-多肽探针靶向整合素αIIbβ3的典型体系开展理论模拟研究，结合具体实验，系统讨论探针与靶蛋白特异性相互作用的关键结合模式以及结合稳定性，揭示探针靶向检测的分子机制。我们采用唯一靶向αIIbβ3的新一代配体γC多肽构建初始探针，在此基础上，有针对性的设计构建系列具有优化靶向性能的新型Au团簇-多肽探针。上述结果为解决活细胞靶向检测的核心科学问题奠定基础。另外，因整合素与重大疾病密切关联，本研究将有助于相关疾病的早期诊断和及时治疗，所以具有重要的实用价值。

本项目目标是运用分子模拟理论研究手段，设计构建Au团簇-多肽探针的分子结构，将典型膜蛋白整合素αIIbβ3 作为靶蛋白设计构建靶向Au团簇-多肽探针体系，实现对这类分子标志物的靶向检测，为新型贵金属团簇-多肽探针设计开发提供科学依据。本项目已顺利完成全部研究内容，已完成：Au团簇-多肽体系本身的Au原子/保护多肽界面研究，筛选原位合成、结合Au团簇氨基酸序列，明确小肽配体对Au团簇分子结构的影响作用，提出利用配体调整Au团簇分子结构、进而调控Au团簇物理化学性质的普适方法；Au团簇-多肽探针与目标蛋白之间的纳米探针/蛋白结合位点界面研究，实现与肿瘤发生发展密切相关的膜蛋白αIIbβ3整合素的特异性检测，并完成另一种重要肿瘤相关膜蛋白EGFR的靶向结合。综上，建立从电子尺度、到原子分子尺度“自下而上”的分子模拟框架，完成Au团簇-多肽探针分子结构设计构建，实现肿瘤相关蛋白的靶向检测，为肿瘤的诊断、治疗提供新的思路。